Sofosbuvir (formerly PSI-7977 or GS-7977) is an approved drug for the treatment of hepatitis C. It was discovered at Pharmasset and then acquired for development by Gilead Sciences. Sofosbuvir is a prodrug that is metabolized to the active antiviral agent 2′-deoxy-2′-a-fluoro-β-C-methyluridine-5′-monophosphate. It is a nucleotide analogue inhibitor of the hepatitis C virus (HCV) polymerase.
Nucleoside phosphoramidate are inhibitors of RNA-dependent, RNA viral replication and are useful as inhibitors of HCV NS5B polymerase, as inhibitors of HCV replication and for treatment of hepatitis C infection in mammals.
Sofosbuvir is chemically known as isopropyl (2S)-2-[[[(2R,3R,4R,5R)-5-(2,4-dioxopyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydrofuran-2-yl] methoxy-phenoxy-phosphoryl] amino] propanoate of Formula (I).

Sofosbuvir was first described in Example 25 of U.S. Pat. No. 7,964,580 B2, which corresponds to WO 2008/121634 A2 and also discloses other novel nucleoside phosphoramidates and their preparations and use as agents for treating viral diseases.
The process disclosed is provided below. The compound of formula VI is protected with a benzoyl group in the presence of benzoyl chloride and pyridine base to obtain the compound of formula V. The amino group of compound V is deprotected in the presence of 80% AcOH under reflux conditions and ammonia/methanol as a solvent was added to get a compound of formula III. The compound of formula III is reacted with a compound of formula IIa to obtain a diastereomeric mixture at “P” of Sp and Rp sofosbuvir. This on chiral resolution by Supercritical Fluid Chromatography (SFC) using 20% MeOH in CO2 as a solvent yields sofosbuvir (I).
The process described herein leads to the production of nucleoside phosphoramidate prodrugs with less than 50% of the desired isomer, which requires additional purifications to get the desired isomer, which enhances the number of steps and cost. This reference does not provide a particular combination of solvents and bases which provides or increases the stereo selectivity during the reaction for the production of the desired Sp isomer.
The above process is schematically shown below.

PCT publication no. WO 2011/123645 A2 discloses various crystalline forms and a process for the preparation of (S)-isopropyl 2-(S)-(((2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-1-(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-amino)propanoate (sofosbuvir), shown below. A compound of formula (V) is deprotected in the presence of 70% AcOH followed by hydrolysis to obtain a compound of formula III. This is reacted with a compound of formula (II) in the presence of a Grignard reagent to obtain sofosbuvir.

The condensation reaction of the compound of formula (III) with the compound of formula (II) in the presence of a Grignard reagent has low yield and a high impurity profile.
Hence, the use of a Grignard reagent may not be feasible and it is not economical for industrial scale production for the preparation of Sofosbuvir (I).
PCT publication no. WO 2006/012440 A2, WO 2008/045419 A1, WO 2006/031725 A2 and U.S. Pat. Nos. 7,601,820 B2 and 8,492,539 B2 disclose processes for the preparation of intermediates, which can be used for the preparation of sofosbuvir.
PCT publication no. WO 2010/135569 A1 discloses various processes for the preparation of sofosbuvir and its intermediates.
PCT publication no. WO 2014/08236 A1 discloses a process for the preparation of diastereomerically enriched phosphoramidate derivatives. WO 2014/047117 A1, CN103804446A and WO2014/056442 A1 disclose various processes for the preparation of intermediates and nucleoside phosphoramidates compounds.
In view of the foregoing, the present inventors have performed extensive experiments and found that sofosbuvir can be produced in high yield and purity in a simple, efficient, more economical and eco-friendly process.